NM_000016.6(ACADM):c.526G>A (p.Ala176Thr) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001002215.15

Allele description [Variation Report for NM_000016.6(ACADM):c.526G>A (p.Ala176Thr)]

NM_000016.6(ACADM):c.526G>A (p.Ala176Thr)

Gene:

ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_000016.6(ACADM):c.526G>A (p.Ala176Thr)

HGVS:

NC_000001.11:g.75740037G>A
NG_007045.2:g.20680G>A
NM_000016.6:c.526G>AMANE SELECT
NM_001127328.3:c.538G>A
NM_001286042.2:c.418G>A
NM_001286043.2:c.625G>A
NM_001286044.2:c.-42G>A
NP_000007.1:p.Ala176Thr
NP_001120800.1:p.Ala180Thr
NP_001272971.1:p.Ala140Thr
NP_001272972.1:p.Ala209Thr
LRG_838:g.20680G>A
NC_000001.10:g.76205722G>A
NM_000016.4:c.526G>A

Protein change:

A140T

Links:

dbSNP: rs200754053

NCBI 1000 Genomes Browser:

rs200754053

Molecular consequence:

NM_001286044.2:c.-42G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000016.6:c.526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.538G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Medium-chain acyl-coenzyme A dehydrogenase deficiency (ACADMD)
Synonyms:: CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY; MCADD; Medium chain acyl-CoA dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0008721; MedGen: C0220710; Orphanet: 42; OMIM: 201450

Recent activity

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Mus musculus chromosome 3, clone RP24-84L9, complete sequence
Mus musculus chromosome 3, clone RP24-84L9, complete sequence
gi|60650507|gnl|WIBR|L24317|gb|AC11 10|

Nucleotide
Homo sapiens partner of NOB1 homolog (S. cerevisiae), mRNA (cDNA clone IMAGE:387...
Homo sapiens partner of NOB1 homolog (S. cerevisiae), mRNA (cDNA clone IMAGE:3876517), partial cds
gi|17390335|gb|BC018152.1|

Nucleotide
Adenylyl Cyclases
Adenylyl Cyclases
Enzymes of the lyase class that catalyze the formation of CYCLIC AMP and pyrophosphate from ATP.<br/>Year introduced: 2016(1968)

MeSH
Chromosome neighbors for GEO Profiles (Select 6190639) (20)
GEO Profiles
Taxonomy Links for GEO Profiles (Select 83050809) (1)
Taxonomy

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001160089	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Nov 15, 2018)	germline	clinical testing	Citation Link,
SCV002171276	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18241067, 20036593, 20434380, 28492532
SCV004216296	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 21, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001160089

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Nov 15, 2018)

germline

clinical testing

Citation Link,

SCV002171276

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004216296

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 21, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population.

Nichols MJ, Saavedra-Matiz CA, Pass KA, Caggana M.

Am J Med Genet A. 2008 Mar 1;146A(5):610-9. doi: 10.1002/ajmg.a.32192.

PubMed [citation]

PMID:: 18241067

Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.

Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA, Erbe R, Devincentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, Caggana M.

Mol Genet Metab. 2010 Mar;99(3):263-8. doi: 10.1016/j.ymgme.2009.10.188. Epub 2009 Nov 1.

PubMed [citation]

PMID:: 20036593

See all PubMed Citations (5)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160089.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ACADM c.526G>A; p.Ala176Thr variant, also known as Ala151Thr, has been described in the compound heterozygous state in individuals affected with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, presenting with elevated octanoylcarnitine (C8) levels (Arnold 2010, Nichols 2008, Smith 2010). It contains an entry in ClinVar (Variation ID: 495343), and is present on only 3 alleles in the Genome Aggregation Databases, indicating it is not a common polymorphism. The alanine at codon 176 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Arnold G et al. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Mol Genet Metab. 2010 Mar;99(3):263-8. Nichols M et al. Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population. Am J Med Genet A. 2008 Mar 1;146A(5):610-9. Smith E et al. Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab. 2010 Jul;100(3):241-50.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002171276.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 176 of the ACADM protein (p.Ala176Thr). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with ACADM-related conditions and/or medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18241067, 20036593, 20434380; Invitae). ClinVar contains an entry for this variant (Variation ID: 495343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function with a positive predictive value of 80%. This variant disrupts the p.Ala176 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004216296.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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